Novel 15-substituted prostanoic acids and esters

ABSTRACT

This disclosure describes compounds of the class of 15substituted-9-keto(or 9-hydroxy)prostanoic acids and the esters and cationic salts thereof, useful as inhibitors of gastric acid secretion.

United States Patent [191 [111 3,835,179 Schaub et al. Sept. 10, 1974 NOVEL IS-SUBSTITUTED PROSTANOIC [58] Field of Search 260/408, 514, 410.9, 413

ACIDS AND ESTERS [75] Inventors: Robert Eugene Schaub, Upper References Cited Saddle River; Martin Joseph Weiss, OTHER PUBLICATIQNS Oraden both of Hine, Physical Organic Chemistry, 2nd Ed., pp. [73] Assignee: American Cyanamid Company, 126-127 (1962).

Stamford, Conn. 22 Filed; July 24 1972 Primary Examiner-Robert Gerstl Attorney, Agent, or FzrmEdward A. Conroy, Jr. [21] App]. No.: 274,558

[57] ABSTRACT [52] 323 2 This disclosure describes compounds of the class of 260/456 R 260/456 26O/464 26O/468 l5-substituted-9-keto(or 9-hydroxy)prostanoic acids and the esters and cationic salts thereof, useful as in- 260/468 J, 260/488 R, 260/501.1, 260/501.2, hibitors of gastric acid secretion 260/514 D, 260/566 AE [51] Int. Cl. C07c 101/30, C070 101/34 10 Claims, No Drawings 1 NO EL .5.- UB S.T. IUIED..BRQSTANO AC DS AND ESTERS I BRIEF SUMMARY OF THE INVENTION This invention relates to novel organic compounds related to the prostaglandin hormones. In particular, the compounds of this invention are l5-substituted-9- keto(or 9-hydroxy)prostanoic acids, their derivatives and congeners, and certain intermediates for the preparation of same. These compounds may be represented by the following general formula:

and H radicals. Suitable lower alkyl and lower alkanoyl groups contemplated by the present invention are those having up to'4 carbon atoms such as methyl, ethyl, isopropyl, sec-butyl, formyl, acetyl, isobutyryl, etc. Halogen is exemplified by chloro, bromo, and iodo.

Also embraced within the scope of the present invention are the non-toxic, pharmaceutically acceptable salts of the l-substituted-9-oxo(or 9- hydroxy)prostanoic acids when R is hydrogen in the above general formula. The cations comprised in these salts include, for example, the non-toxic metal cations such as the sodium ion, potassium ion, calcium ion, and magnesium ion as well as the organic amine cations such as the tri(lower alkyl)amine cations, (e.g., triethylamine), procaine, and the like.

The novel l5-substituted-9-oxo(or 9- hydroxy)prostanoic acids and esters thereof of the present invention are obtainable as yellow oils having characteristic absorption spectra. They are relatively insoluble in water but are relatively soluble in common organic solvents such as ethanol, ethyl acetate, dimethylformamide, and the like. The cationic salts of the l5-substituted-9-oxo(or 9-hydroxy)prostanoic acids are. in general, white to yellow crystalline solids having characteristic melting points and absorption spectra. They are relatively soluble in water, methanol, and ethanol but are relatively insoluble in benzene, diethyl ether, and petroleum ether.

DETAILED DESCRIPTION OF THE lNVENTlON The prostaglandins are a family of closely related compounds which have been obtained from various animal tissues, and which stimulate smooth muscle, lower arterial blood pressure, antagonize epinephrineinduced mobilization of free fatty acids, and have other pharmacological and autopharmacological effects in mammals. See Bergstrom. et al., J. Biol. Chem. 238,

2 3555 (i963) and Horton, Experientia 21, 113 (1965) and references cited therein. All of the so-called natural prostaglandins are derivatives of prostanoic acid:

CH1 on; on, ca FE o c o cm CH1 CH1 CH1 The hydrogen atoms attached to C-8 and C12 are in trans configuration.

The novel compounds of this invention are prepared in accordance with the following reaction scheme:

O-C (CH3):

ll ll wherein R, and m as hereinbefore defined, R' is an alkyl group having from 1 to 12 carbon atoms, preferably methyl or ethyl, R is a lower alkyl group, X is selected from the group consisting of halogen. lower alkanoylthio, and azido radicals.

in accordance with the above reaction scheme, the conjugate l,4-addition of a 3-(substituted hydroxy)alkyl magnesium halide (II) to an alkyl ester (l) of Z-(wcarboxyalkyl)cyclopent-Z-en- 1 -one is carried out in the presence of a catalyst such as the tributylpliosphinecuprpus iodide complex; (C H P'Cul. This reaction is best carried out in the usual way in an ether-type solvent such as diethyl ether, dibutyl ether, tetrahydrofuran, and the like, at room temperature for a period of time of from 2 to 18 hours. The intermediate magnesium halide-enolate adduct is then hydrolyzed in situ, preferably with ammonium chloride, at room temperature and the product (III) is isolated in the usual manner well known in the art.

Removal of the O-t-butyl blocking'group from (III) to afford (IV) is conveniently effected by treatment with glacial trifluoroacetic acid at from -5 to C. for a period of l to 3 hours. Since this procedure may lead to partial trifluoroacetylation of the free hydroxy function, it is preferably followed by treatment with aqueous ammonia (about LON concentration) for about minutes at ambient temperatures. In order to ensure the formation of the depicted trans relationship between the two side-chains, the product can be further treated under alkaline or acidic conditions known to promote equilibration to the thermodynamicallyfavored trans relationship. Such conditions include treatment with potassium acetate in aqueous methanol for 96 hours at room temperature.

For the introduction of the various groups embraced by the above definition of X the IS-hydroxy derivative (IV) is converted to the corresponding l5-alkylsulfonyloxy derivative (V) in the psual manner by reaction with an alkyl sulfonic acid chlo rid e, preferably methanesulfonyl chloride. Displacement of the sulfonyloxy function by reaction with metal halides, sodium azide, potassium thiocyanate and the potassium salt of a lower thioalkanoic acid provides the novel compounds of this invention defined by formula (VI). Further transformation provides other of the novel compounds of this invention. Thus, catalytic hydrogenation of the l5-azido derivative (VI, X=N gives the IS-amino derivative (VII), and methanolic methoxide treatment of the IS-acetylthio derivative gives the l5-mercapto derivative (VIII). Careful saponification of (VI), (VII), or (VIII) provides the carboxylic acids of this invention and reesterification provides other of the esters of this invention.

The 9-keto derivatives (IX) of this invention can be converted to the 9-hydroxy derivatives. If this conversion is effected with sodium borohydride, the product is a mixture of 9aand 9B-hydroxy derivatives (XI XII). When the reaction is carried out with lithium perhydro-9b-boraphenalyl hydride (X) [H. C. Brown and W. C. Dickason, Joum. Amer. Chem. Soc, 92, 709 (l970)], the product is at least predominantly the 9ahydroxy derivative (XI), wherein the 9-hydroxy group is cis to the adjacent side-chain bearing the carboxylic acid or ester function.

tomn-b-o-n,

(XII) All of the compounds of this invention can be isolated and purified by conventional methods. Isolation can be accomplished, for example, by dilution of the reaction mixture with water, extraction with a waterimmiscible solvent such as methylene chloride, ethyl acetate, benzene, cyclohexane, ether, toluene and the like, chromatography, adsorption on ion-exchange resins, distillation, or a combination of these. Purification of the compounds of this invention can be accomplished by means known in the art for the purification of prostaglandins and lipids, fatty acids, and fatty esters. For example, reverse phase partition chromatography, countercurrent distribution adsorption chromatography'on acidwashed Florisil@(synthetic magnesium silicate) and acid washed silica gel, preparative paper chromatography, preparative thin layer chromatography, chromatography over silver loaded cation exchange resins, and combinations thereof can be used effectively to purify the compounds produced by the processes of this invention.

All the novel compounds of this invention having assymmetric carbon atoms can be produced as racemic mixtures. These racemic mixtures can be resolved at appropriate stages bymethods of resolution well known in the art. For example, acids can be treated with an optically active base such as cinchonine, quinine, brucine, dor l-a-phenylethylamin.e and the like to produce diasteroisomeric salts which can be separated by crystallization. Alternatively, the acid may be esterified with an optically active alcohol, e.g., dor I- menthol, estradiol 3-acetate, etc., and the diastereoisomeric esters then resolved.

Resolution of the racemic prostaglandin-like compounds of this invention can also be accomplished by reverse phase and absorption chromatography on an optically active support and adsorbent and by selective transformation of one isomer with a biologically-active prostaglandin transforming system. Such transformations can be carried out by incubation or perfusion using methods well established in the art, followed by isolation and recovery of the isomer resistant to the metabolic transformation applied. It is to be understood that the pictorial representation of the compounds of the present process is to-be construed as inclusive of other forms including enantiomers and racemates, and not to be construed as limited to the particular forms shown.

It is also possible to prepare certain of the possible diastereomers by appropriate transformation from isomerically pure starting materials, in particular compounds (XIII) and (XIV), which are available from the sea coral Plexaura homomalla and which correspond to compound (IV) above.

Compound (XIII) has all its asymetric carbon atoms in the same configuration as found in the mammalian prostaglandins and is obtained by total hydrogenation of the prostaglandin A diester (XV) followed by saponification and reesterification. Compound (XIV) which has the 15R configuration has been reported by R. E. Spraggins [Dissertation submitted to the University of Oklahoma, 1970; Dissertation Abstracts 31, 3934B (1971)] and is prepared in the same way as (XIII) from the 15R diastereomer corresponding to (XV).

cam-c 01cm O K H v (CH2) u-C OzOHg The products of this invention have potential utility as hypotensive agents, agents for the inhibition of platelet aggregating, bronchodilators, antimicrobial agents, anticonvulsants, abortifacients, agents for the induction of labor, agents for the induction of menses, fertility-controlling agents, central nervous system regulatory agents, salt and water-retention regulatory agents, diuretics, fat metabolic regulatory agents and as serumcholesterol lowering agents. Certain of the novel compounds of this invention possess utility as intermediates for the preparation of other of the novel compounds of this invention.

The compounds of this invention are effective inhibitors of gastric acid secretion and of ulcer development in experimental animals and thus are potentially valuable as agents for the control of gastric acid secretion, gastric erosion, and as anti-ulcer agents.

Gastric acid secretion inhibitory action is usually measured by the Shay" techniques with some modification. [Shay, H., Sun, D. and Gruenstein, M.: A quantitative method for measuring spontaneous gastric secretion in the rat, Gastroenterology 26: 906-913 (1954); Shay, H., Komarov, S.A., Fels, S.S., Meranze, D., Gruenstein, M. and Siplet, H.: A simple method for the uniform production of gastric ulceration in the rat," Gaslmenrerology 5: 43-61 (1945)]. The Shay rat assay has been cited in a recent authoritative review as probably the best single test for prediction of clinical usefulness [Brodie, Gastroenterology, 58, 125-134 1968)].

This procedure as adapted in our laboratories was carried out as follows. The rats male, CF E strain) were starved for 48 hours (water was given ad libitum) to permit evacuation of stomach contents. On the morning of the experiment, under ether anesthesia, the abdominal region was shaved and a midline incision (1-1 /2 inches) was made with a scalpel. With the help of a closed curved hemostat the duodenum was picked up. Upon getting the duodenum into view, fingers were used to pull the stomach through the opening, the stomach was then gently manipulated with fingers to rid stomach of air and residual matter which were pushed through the pylorus. (This manipulation provides for enhanced and uniform acid secretion.) Two 5-inch sutures were drawn under the pyloric-duodenal puncture. A ligature, at the juncture, was formed with one of the threads. A second ligature was also formed but not tightened.

omcm-E- omxom 5 The test compounds or the vehicle (usually 1 mL/ 1 00 g. body weight) were injected into the duodenum as close as possible to the first ligature. After injection the second ligature was tightened below the injection site to minimize leakage. The stomach was placed back through the opening into the abdominal cavity, the area of incision was washed with saline and'the incision was closed with autoclips.

Three hours later, the rats were decapitated and exsanguinated, taking care that blood does not drain into the esophagus. The abdominal cavity was exposed by cutting with scissors and the esophagus close to the stomach was clamped off with a heomstat, the stomach was removed by cutting above the hemostat (the esophagus was cut) and between the two sutures. Extraneous tissue was removed, the stomach washed with saline and blotted on gauze. A slit was carefully made in the stomach held over a funnel and the contents were collected in a centrifuge tube. The stomach was further cut along the outside edge and turned insideout. Two ml. of water were used to wash the stomach contents into the respective centrifuge tube. The combined stomach contents and wash were then centrifuged out for 10 minutes in the International Size 2 Centrifuge (setting at 30). The supernatant was collected, volume measured and recorded, two drops of a phenolphthalein indicator 1 percent in percent ethanol) were added and the solution was titrated with 0.02N NaOH (or with 0.04N NaOH when large volumes of stomach contents were encountered) to pH 8.4 (because of usual coloring of the stomach contents, phenolphthalein was merely used to permit visual indication that the end point was near) and the amount of acid present was calculated. Compounds inducing inhibition of gastric acid secretion of 20 percent or more are considered active. Representative results obtained with this assay are given in the following Table.

TABLE 1 Inhibition of Gastric Acid Secretion in the Pylorus ligated Rat (Shay-Rat") /r lntraduodenal Inhi- Compound Dose. mg./kg. bition Ethyl 9-oxo-l5-azidoprostanoate 52 9-Oxo-15-azidoprostanoic Acid 100 30 Ethyl 9-oxo-IS-mercaptoprostanoate 200 32 Ethyl 9-oxo-lS-chloroprostanoate 100 24 Ethyl 9-oxo-15-thiocyanoprostanoate 100 57 This invention will be described in greater detail in conjunction with the following specific examples.

EXAMPLE 1 Preparation of I 2-carba1koxy(methyl/ethyl)-2-(4-carbethoxybuty1)- cyclopentan- 1 -one The mixture is cooled and filtered. The solvent is removed from the filtrate by evaporation and the residue is poured into dilute hydrochloric acid and extracted with ether. The combined extracts are washed with water and saline, dried over magnesium sulfate and evaporated to give an oil. The oil is distilled under reduced pressure to give 274 g. of a light yellow oil, b.p. l40l43C. (0.17 mm).

EXAMPLE 2 Preparation of 2-(4-carboxybutyl)cyclopentan- 1 -one A stirred mixture of 274 g. of 2-carbalkoxy(mixed methyl and ethyl esters)-2-(4-carbethoxybutyl)cyclopentan-l-one (Example. 1), 600 ml. of 20 percent hydrochloric acid and 325 ml. of acetic acid is heated at reflux for 20 hours. Solution occurs in approximately one-half hour. The solution is cooled and diluted with water and extracted with ether. The combined extracts are washed with saline and dried over magnesium sulfate and evaporated. The residue is evaporated twice with toluene to give 144 g. of an oil.

EXAMPLE 3 Preparation of 2-(4-carbethoxybutyl)cyclopentan- 1 -one A stirred solution of 124 g. (0.673 mole) of 2-(4- carboxybutyl)cyclopentan-l-one (Example 2), 800 ml. of ethanol and l g. of p-toluenesulfonic acid monohydrate is heated at reflux for 18 hours. The solvent is evaporated and the residue is dissolved in ether. The ether solution is washed with saline, dilute sodium bicarbonate solution and again with saline, dried over magnesium sulfate and evaporated. The oil is distilled under reduced pressure to give 149 g. of a colorless oil, b.p. lO6-109C. (0.23 mm).

EXAMPLE 4 Preparation of 2-carbalkoxy( methyl/ethyl )-2-( 3-carbethoxypropyl cyclopentan- 1 one In the manner described in Example 1, treatment of Z-cyclopentanone carboxylate (mixed methyl and ethyl esters) with sodium hydride in dimethoxyethane followed by ethyl 4-iodobutyrategives a yellow oil, b.p., l36l37C. (0.16 mm).

EXAMPLE 5 Preparation of 2-(3-carboxypropyl)cyclopentan-l-one In the manner described in Example 2. treatment of 2-carbalkoxy(mixed methyl and ethyl esters)-2-(3- carbethoxypropyl)cyclopentan-1-one (Example 4) with a percent hydrochloric acid and acetic acid mixture gives a yellow oil.

EXAMPLE 6 Preparation of 2-( 3-carbethoxypropyl )cyclopentan- 1 -one In the manner described in Example 3, treatment of 2-( 3-carboxypropyl )cyclopentan- 1 -one (Example 5) with p-toluenesulfonic acid monohydrate in ethanol gives a colorless oil, b.p. 93C. (0.10 mm).

EXAMPLE 7 Preparation of ethyl and methyl 2-( o-carbethoxyhexyl l -cyclopentanon-2-carboxylate In the manner described in Example 1. ethyl and methyl 2-cyclopentanone carboxylate is reacted with ethyl 7-bromoheptanoate to furnish the subject product, b.p. 147C. (0.09 mm).

EXAMPLE 8 Preparation of 2-(6-carboxyhexyl)cyclopentan- 1 -one In the manner described in Example 2, ethyl and methyl 2-( 6-carbethoxyhexyl 1 -cyclopentanone-2- carboxylate (Example 7).is hydrolyzed to furnish the subject product, b.p. 143C. (0.05 mm).

EXAMPLE 9 Preparation of 2-( -carbethoxyhexyl )cyclopentan- 1 -one In the manner described in Example 3, 2-(6- carboxyhexyl)cyclopentan- 1 -one (Example 8) is esterified to furnish the subject product, b.p. 1 10C. (0.03 mm).

EXAMPLE 10 Preparation of l-acetoxy-2-(6-carbethoxyhexyl)cyclopent-1-ene A stirred solution of g. of 2-(6-carbethoxyhexyl)- cyclopentan-l-one (Example 9) in 250 ml. of acetic anhydride containing 0.940 g. of p-toluenesulfonic acid monohydrate is heated to boiling under partial reflux allowing distillate at 118C. or less, (i.e., acetic acid) to escape through a Vigreaux column equipped with a condenser to collect the distillate. After 16 hours, during which period acetic anhydride is added in portions in order to keep the solvent level at at least 100 ml., the solution is cooled and poured cautiously into a stirred cold mixture of saturated sodium bicarbonate solution (400 ml.) and hexane (250 ml.). The resulting mixture is stirred for an additional 30 minutes during which period solid sodium bicarbonate is added periodically to insure a basic solution. The hexane layer is separated and washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness. Distillation of the residual oil gives 102 g. (87 percent) of pale yellow oil, b.p. l 18C. (0.07 mm).

EXAMPLE 1 1 Preparation of l-acetoxy-2-( 3-carbethoxypropyl )cyclopent- 1 -ene In the manner described in Example 10, treatment of 2-( 3-carbethoxypropyl )cyclopentan- 1 -one (Example 6) with acetic anhydride and p-toluenesulfonic acid monohydrate gives a yellow oil, b.p. 98l03C. (0.35 mm).

EXAMPLE 12 Preparation of l-acetoxy-2-( 4-carbethoxybutyl )cyclopentl -ene In the manner described in Example 10, treatment of 2-(4-carbethoxybutyl)cyclopentan-l-one (Example 3) with acetic anhydride and p-toluenesulfonic acid monohydrate gives a yellow oil, b.p. l09-1 10C. (0.37 mm).

EXAMPLE 13 To a rapidly stirred mixture of 50 g. of 1-acetoxy-2- (6-carbethoxyhexyl)cyclopent-1-ene (Example 10) in 150 ml. of chloroform, 200 ml. of water and 18.8 g. of calcium carbonate, cooled in an ice bath, is added dropwise over a period of about 30 minutes, a solution of 30 g. of bromine in 50 m1. of carbon tetrachloride. After stirring for an additional 45 minutes the chloroform layer is separated and washed successively with dilute sodium thiosulfate solution, saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness under reduced pressure.

The residual oil is dissolved in 50 ml. of N,N-dimethylformamide and added to a mixture of 33 g. of lithium bromide and 32 g. of lithium carbonate in 375 ml. of N,Ndimethylformamide, previously dried by refluxing with 375 ml. of benzene under a Dean-Stark apparatus followed by distillation of the benzene. The mixture is stirred at the reflux temperature for 30 minutes, then cooled and poured into 850 ml. of ice-cold water. The resulting mixture is acidified (cautiously) with 4N hydrochloric acid and extracted with ether three times. The combined ether extracts are washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness under reduced pressure to afford 41.5 g. of an amber oil. In order to convert any isomeric material to the desired product, 41.5 g. of the above material is treated with 0.500 g. of p-toluenesulfonic acid monohydrate in 450 ml. of absolute alcohol at the reflux temperature for 18 hours. The solution is taken to dryness under reduced pressure. The resulting gum is dissolved in ether and washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness under reduced pressure. The residual oil is distilled to give 30.2 g. of product; b.p. 118C. (0.05 mm); x,,,,,, 229 mp. 69950 x,,,,,,, 5.75, 5.85, 6.15, 8.45 t; vapor phase chromatography shows 99 percent product, containing 1 percent 2-(6- carbethoxyhexyl )cyclopentan-l -one.

This product can be purified by the following procedure. A mixture of 120 g. of 2-(6-carbethoxyhexyl)-2- cyclopentenone, containing approximately 5 percent of the saturated analogue, and 7.67 g. mole percent) of p-carboxyphenylhydrazine in 400 ml. of absolute ethanol is stirred at ambient temperatures for 18 hours and is then refluxed for 1 hour. The mixture is cooled, the solvent is evaporated, and the residue is taken up into 150 ml. of chloroform and passed through a column of 450 g. of aluminum oxide (Merck). The filtrate is evaporated to yield a colorless oil containing 0.5 percent of the saturated impurity.

EXAMPLE 14 Preparation of 2-( 3-carbethoxypropyl )cyclopent-Z-en- 1 -one In the manner described in Example 13, bromination of l-acetoxy-2-( 3-carbethoxypropyl)cyclopentl -ene (Example ll) followed by dehydrobromination with lithium bromide and lithium carbonate is productive of the subject compound.

EXAMPLE 1 5 Preparation of 2-(4-carbethoxybutyl)cyclopent-Z-en- 1 -one In the manner described in Example 13, treatment of l-acetoxy-2-(4-carbethoxybutyl )cyclopentl -ene (Example 12) with bromine and subsequent treatment of the brominated product with a mixture of lithium bromide and lithium carbonate in N,N-dimethylformamide is productive of the subject compound. Treatment of this product with p-carboxyphenylhydrazine by the procedure of Example 13 furnishes a product which contains less than 0.5 percent of the corresponding saturated ketone.

EXAMPLE 16 Preparation of 1-methoximino-2-(6-carbethoxyhexyl)-2-cyclopentene To a mixture of 35.97 g. (0.151 mole) of 2-(6- carbethoxyhexyl )-2-cyc1opentenone (Example 13) and 15.0 g. (0.180 mole) of methoxyamine hydrochloride in 300 ml. of absolute ethanol is added 25 ml. of pyridine and the resulting solution is stirred for 20 hours at ambient temperatures. The solvent is evaporated and the residue is partitioned between water and diethyl ether. The organic phase is washed with water and saturated brine, dried (Na SO and the solvent is evaporated to yield an oil. Distillation yields 38.7 g. of a colorless oil, b.p. l151l8C. (0.075 mm). IR (film): 1740, 1627, 1053, 890 cm A (MeOH) 243 (13,000). NMR8(CDC1 3.89.

EXAMPLE 17 Preparation of 1-methoximino-2-(7-hydroxyheptyl )-2-cyclopentene To an ice cooled solution of 34. 10 g. (0.128 mole) of l-methoximino-2-( 6-carbethoxyhexyl)-2-cyclopentene (Example 16) in 200 ml. of benzene under nitrogen is added dropwise 225 ml. of a 25 percent solution of diisobutyl aluminum hydride in hexane. The resulting solution is stirred for 2 hours at 05C., poured onto ice and dilute hydrochloric acid, and the aqueous phase is saturated with sodium chloride. The organic phase is separated, washed with saturated brine, dried (Na;'. S0,), and evaporated to yield an oil. The latter is dissolved in ml. of hot hexane and cooled to yield 24.3 g. of crystals, m.p. 6264C. 1R (KB'r) 3260, 1630, 1059, 893 cm k 243 (14,200). NMR (CDCl )8: 2.37.

EXAMPLE 18 Preparation of l-methoximino-2-(7-p-toluenesulfonyloxyheptyl)-2- cyclopentene To a solution of 5.00 g. (0.0222 mole) of lmethoximino-2-( 7-hydroxyheptyl )-2 -cyclopentene (Example 17) in 50 m1. of dry pyridine at 0C. is added 8.45 g. (0.0444 mole) of p-toluenesulfonyl chloride and the resulting solution is chilled at 5C. overnight. The mixture is partitioned between 300 ml. of ice water and diethyl ether. The organic phase is washed with 1:1 ice cold hydrochloric acid, cold water, and cold saturated brine, dried (NaSO /K CO and evaporated under reduced pressure at room temperature to yield an oil. The latter is dissolved in 600 ml. of hexane,

treated with 0.5 g. of Darco, filtered and evaporated to yield 7.7 g. of a colorless oil. 1R (film) 1600, 1192, 1182, 1053, 890 cm A (MeOH) 228 and 243.

EXAMPLE 19 Preparation of 1-methoximino-2-( 8 ,8-dicarbethoxyoctyl )-2- cyclopentene To an alcoholic solution of sodiodiethyl malonate, prepared from 0.847 g. (0.0368 g. atoms) of sodium, 100 ml. of absolute ethanol, and 7.05 g. (0.0440 mole) of diethyl malonate is added 7.7 g. of the tosylate of Example 18 and the mixture is refluxed for 2 hours under a nitrogen atmosphere. The mixture is partitioned between cold dilute hydrochloric acid and diethyl ether, and the organic phase is washed with water and saturated brine, dried (Na SO and evaporated to yield an oil. The excess diethyl malonate is distilled off under reduced pressure to yield 6.45 g. of a yellowish oil. IR (film) 1755, 1728, 1625, 1054, 890 cm.

EXAMPLE 20 Preparation of 1-methoximino-2-( 8 ,S-dicarboxyoctyl )-2- cyclopentene A mixture of 6.45 g. of the diester of Example 19 and 6.72 g. of potassium hydroxide in 150 ml. of 1:1 aqueous methanol is refluxed for 1 hour, cooled, and is partitioned between water and diethyl ether. The aqueous phase is acidified with hydrochloric acid, extracted with ether, and the organic phase is washed with water and saturated-brine, dried (Na SO and evaporated to yield a solid. The solid is crystallized from benzene to yield 4.15 g. of tan crystals, m.p. l35137C. (CO

EXAMPLE 21 Preparation of 1-methoximino-2-( S-carboxyoctyl )-2-cyclopentene A solution of 3.926 g. (0.0126 mole) of the diacid of Example 20 in 20 ml. of xylene is refluxed for 1.5

hours, cooled. and evaporated to yield a tan solid. IR (KBr) 1720, 1618, 1179, 1050, 986 cm.

EXAMPLE 22 Preparation of 2-(8-carboxyoctyl)cycopent-2-en-1-one The acid methoxime from Example 21 is refluxed for hours with 55 ml. of acetone and 20 ml. of 2N hydrochloric acid. The mixture is cooled, the solvent is evaporated, and the residue is partitioned between water and diethyl ether. The organic phase is washed with water and saturated brine, dried (Na SO and evaporated to yield a tan solid. IR (KBr) 1745, 1665 cm A (MeOH) 228 (12,600).

EXAMPLE 23 Preparation of 2-(8-carbethoxyoctyl)cyclopent-Z-en-1-one The acid ketone from Example 22 is Fisher esterified with 100 ml. of absolute ethanol, 100 ml. of benzene,

and 20 mg. of p-toluenesulfonic acid for 6 hours, cooled, and the solvent is evaporated. The resulting oil is dissolved in 3:1 benzene-ether and the solution is passed through a column of 100 g. of Florisil. The filtrate is evaporated and the residue is distilled to yield 2.97g. ofa colorless oil, b.p. 137139C. (0.05 Torr).

EXAMPLE 24 Preparation of 1-methoximino-2-( S-cyanopentyl )-2-cyclopentene A mixture of 2.75 g. (0.01 mole of l-methoximino-Z- (5-methanesulfonyloxypentyl )-2-cyclopentene (Example 27) and 1.47 g. (0.03 mole) of sodium cyanide in 20 ml. of dry N,N-dimethylformamide is heated at 65-70C. for 3 hours. The cooled reaction mixture is poured into water and extracted with diethyl ether. The organic phase is washed with'water and saturated saline solution, dried (MgSO and evaporated to give 1.89 g. of a light yellow oil.

EXAMPLE 25 Preparation of 1-methoximino-2-( S-carboxypentyl )-2-cyclopentene A mixture of 1.89 g. (0.0092 mole) of 1- methoximino-2-(5-cyanopentyl)-2-cyclopentene (Example 24) and 1 g. (0.025 mole) of sodium hydroxide in 50 ml. of 1:1 aqueous-ethanol is refluxed for 48 hours, cooled, and partitioned between water and diethyl ether. The aqueous phase is acidified with hydrochloric acid, extracted with diethyl ether, and the organic phase is washed with water and saturated saline solution, dried (MgSO and evaporated to give 1.86 g. of a yellow oil.

EXAMPLE 26 Preparation of 2-(5-carboxypentyl)-2-cyclopentenone EXAMPLE 27 Preparation of 2-( 5-carbethoxypentyl )-2-cyclopente none A solution of 1.309 g. (0.00668 mole) of 2-(5- carboxypentyl)-2-cyclopentenone (Example 26) and mg. of p-toluenesulfonic acid in ml. of ethanol is refluxed for 18 hours. The solvent is evaporated and the residue is dissolved in ether. The organic phase is washed with water, sodium bicarbonate solution, and saturated saline solution, dried (MgSO and evaporated to give 1.371 g. of a light yellow oil.

EXAMPLE 28 Preparation of 2-(5-acetoxypentyl)-2-carbomethoxy/carbethoxy cyclopentanone A mixture of sodiocyclopentanone carboxylate, prepared from 1,200 g. (8.0 moles) of cyclopentanone carboxylate (methyl andethyl esters) and 200 g. (8.3

EXAMPLE 29 Preparation of 2-( S-hydroxypentyl )cyclopentanone/2-( -acetoxypentyl)-cyclopentanone A mixture of 4,500 g. (16.2 moles) of 2-(5- acetoxypentyl)-2-carbomethoxy/carboethoxycyclopentanone (Example 28), 2.2 l. of glacial acetic acid, 1 l. of concentrated hydrochloric acid, and l l. of water is refluxed for 18 hours, cooled, and partitioned between saturated brine and benzene. The organic phase is washed with saturated brine, dried (MgSO and evaporated in vacuo to yield 3,155 g. of an oil.

EXAMPLE 30 Preparation of 1 -acetoxy-2-( 5-acetoxypentyl 1 -cyclopentene A solution of 400 g. (2.04 moles) of a mixture of 2- (S-hydroxypentyl )cyclopentanone and 2-( 5- acetoxypentyl)cyclopentanone (Example 29) and 4.0 g. of p-toluenesulfonic acid monohydrate in l l. of acetic anhydride is refluxed at a rate to maintain a steady distillation of acetic acid from the reaction through a helix-packed fractionation column. The reaction is continued with the addition of acetic anhydride to maintain a constant volume until complete conversion of starting materials to product is evident. The mixture is cooled and partitioned between 2 l. of hexane and 3 l. of cold water containing solid sodium bicarbonate to maintain a neutral pH. The organic phase is washed with saturated brine. dried (MgSO and evaporated to yield 452 g. of an oil.

EXAMPLE 31 Preparation of 2-(5-acetoxypentyl)-2-cyclopentenone To a well stirred mixture of 405 g. (4.05 moles) of calcium carbonate, 3 l. of water, and 2.5. l. of chloroform cooled to 5C. is added simultaneously 1,016 g. (4.0 moles) of 1-acetoxy-2-(5-acetoxy-pentyl)-lcyclopentene (Example 30 and a solution of 648 g. (4.05 moles) of bromine in 500 ml. of carbon tetrachloride at a rate to maintain a temperature below C. The mixture is stirred for half an hour after addition of the reagents and the phases are then separated. The organic phase is washed with 2 percent sodium thiosulfate solution, water, and saturated brine, dried (MgSO and evaporated in vacuo to an oil. The oil is immediately added to a refluxing slurry of 500 g. (5.0 moles) of calcium carbonate in 2.5 l. of N,N- dimethylacetamide under nitrogen and the mixture is then refluxed for thirty minutes. The mixture is cooled, filtered, and partitioned between water and diethyl ether. The organic phase is washed with water and saturated brine/dried (MgSO4). and evaporated to yield 757 g. of an oil, b.p. 116118C. (0.25 mm.).

EXAMPLE 32 Preparation of 1 -methoximino-2-( S-acetoxypentyl )-2-cyc1opentene In the manner described for Example 16, 2-(5- acetoxypentyl)-2-cyclopentenone (Example 31) is treated with methoxyamine hydrochloride in pyridine and ethanol to yield the subject compound, b.p. l0l-l03C. (020mm).

EXAMPLE 33.

Preparation of l-methoximino-2-(S-hydroxypentyl)-2-cyclopentene A mixture of 74 g. (0.22 mole) of l-methoximino-2- (S-acetoxypentyl)-2-cyclopentene (Example 32) and 56 g. (1.0 mole) of potassium hydroxide in 300 ml. of 1:1 aqueous methanol is refluxed for 2 hours and then cooled. The solvent is partially removed in vacuo and the residue is partitioned between saturated brine and diethyl ether. The organic phase is washed with saturated brine, dried (MgSO and evaporated to yield an oil with crystallized, m.p. 3536C.

EXAMPLE 34 Preparation of 1-methoximino-2-(5-methanesulfonyloxypentyl)-2- cyclopentene bonate solution, and cold saturated brine. dried (MgSO4). and evaporated to yield a solid, mp. 7889C.

EXAMPLE 35 Preparation of l-methoximino-2-( 6,6-dicarbethoxyhexyl )-2- cyclopentene To a suspension of sodiodiethylmalonate in 1,2- dimethoxyethane, prepared from 248 g. (1.55 moles) of diethyl malonate and 17.2 g. (0.95 mole) of mineral oil free sodium hydride in l l. of 1,2-dimethoxyethane under nitrogen, is added g. (0.62 mole) of 1- methoximino-2-(5-methanesulfonyloxypentyl)-2- cyclopentene (Example 34) in 1.5 l. of 1,2- dimethoxyethane and the mixture is refluxed for 5 hours. The mixture is cooled, filtered, and the solvent is evaporated. The residue is partitioned between cold dilute hydrochloric acid and water, and the organic phase is washed with saturated brine, dried (MgSO and evaporated to remove solvent and excess diethyl malonate to yield 209 g. of an oil.

EXAMPLE 36 Preparation of l-methoximino-2-( 6,6-dicarboxyhexyl )-2- cyclopentene 1n the manner described in Example 20, lmethoximino-2-(6,6-dicarbethoxyhexyl)-2- cyclopentene is treated with potassium hydroxide in 1:1 aqueous methanol and then hydrochloric acid to yield the desired compound as crystals from diethyl ether, m.p. ll115C.

EXAMPLE 37 Preparation of l-methoximino-2-( o-carboxyhexyl )-2-cyclopentene (Example 37) with acetone and 2N hydrochloric acid at reflux provides the subject compound.

EXAMPLE 39 Preparation of 2-(6-carbethoxyhexyl)-2-cyclopentenone Fischer estification of 2-(6-carboxyhexyl)-2- cyclopentenone (Example 38) in the manner of Example 23 provides-the subject compound.

EXAMPLE 40 Preparation of 2-(7-cyanoheptyl)-1-methoximino-2-cyclopentene Treatment of l-methoximino-2-(7-ptoluenesulfonyloxy)-2-cyclopentene (Example 18) with sodium cyanide in the manner of Example 24 is productive of the subject compound.

EXAMPLE 42 Preparation of 2-(7-carboxyheptyl)-2-cyclopenten-1-one Hydrolysis of the methoxime of Example 41 with acetone-hydrochloric acid by the procedure of Example 26 is productive of the subject compound.

EXAMPLE 43 Preparation of 2-( 7-carbethoxyheptyl 2-cyclopenten- 1 -one Fisher estification of the carboxylic acid of Example 42 by the production of Example 27 is productive of the subject compound.

EXAMPLE 44 Preparation of 2-( 6-carbo-n-butoxyhexyl )cyclopent-2-en- 1 -one A solution of 50 g. of 2-(6 carboxyhexyl)cyclopent- 2-en-1-one [Bagli, et al., Tetrahedron Letters, No.

. 16 5,465 (1966)] in 1,400 ml. of n-butanol containing 2.7 g. of p-toluenesulfonic acid monohydrate is allowed to stand at room temperature in a stoppered flask for about 24 hours. The solution is taken to dryness. The residue is taken up in ether and the ethereal solution is washed several times with saline solution, dried with anhydrous magnesium sulfate, and taken to dryness to afford the subject butyl ester.

EXAMPLES 45-47 Treatment of 2-(6 carboxyhexyl)cyclopent-2-enl-one by the procedure of Example 44 with the appropriate alcohol affords the esters of the following table.

TABLEI Example Alcohol Product Ester 45 isopropanol 2-(-carboisopropoxyhexyl) cyclopent-Z-en-l-one 46 methanol 2-(6-carbomethoxyhexyl)cyclopent- 2-en-l-one 47 l-hydroxy- 2-(6-carbo-n-decyloxyhexyl) -n-dccane cyclopent-Z-en-l-one EXAMPLE 48 Preparation of 3-(tert-butoxy)-l-iodooctane Into a solution of 16.7 g. of l-iod0-3-octanol [Shriner, et al., J. Org. Chem. 4, 103 (1939)] in 250 ml. of methylene chloride is bubbled isobutylene at a fast rate until the solution is saturated. The solution is cooled and 2 ml. of concentrated sulfuric acid is added. The solution is stoppered and allowed to stand at room temperature for 3 days. After the solution is poured into 300 ml. of 5 percent sodium carbonate, the organic phase is separated, washed with brine, dried with anhydrous magnesium sulfate and evaporated to dryness. Distillation gave 13.9 g. (68 percent) of product, b.p. 59C. (0.008 mm).

EXAMPLE 49 Preparation of l5-(tert-butoxy)-9-oxoprostanoic acid,

ethyl ester To a Grignard solution, prepared from 5.05 g. of magnesium and 65.8 g. of 3-(tert-butoxy)-1- iodooctane in 150 ml. of diethyl ether under nitrogen atmosphere, is added 4.0 g. of copper iodide-tri-nbutylphosphine complex followed by dropwise addition of 49 g. of 2-(6-carbethoxyhexyl)cyclopent-Z-en-l-one [Hardegger, et al., Helv. Chim. Acta 50, 2501 (1967)] and the resulting mixture is stirred for 18 hours. Saturated ammonium chloride (1 10 ml.) is added followed by 100 ml. of water and 100 ml. of diethyl ether, Unreacted magnesium is removed by filtration. The ethereal layer is washed successively with aqueous sodium thiosulfate solution, ammonium chloride solution, and water, dried over magnesium sulfate and taken to dryness to give an oil. Distillation at 0.05 mm. (bath 100-l C.) gives 45.4 g. of material containing unreacted starting material and 30 g. (85 percent yield based on non-recovered starting material; see below) of residue which contains the desired product. This material is chromatographed on silica gel. The product is eluted with diethyl ether to give 25.2 g. (71 percent based on recovered starting material) of a syrup; this 17 material has no significant ultraviolet absorption; A KBr/max 5.74, 7.20, 7.35, 8.35 a; nmr 2H quartet 3 4.09 (OCH of ester), 1H broad singlet 3.57 (carbinolic proton), 5H overlapping multiplets 2.0-2.4 (protons next to C=O), 3H triplet 1.22 (CH, of ethyl), 9H singlet 1.17 (CH s to t-butyl) and 3H triplet 0.9 (terminal methyl); mass spectrum: m/e 424.

EXAMPLE 50 Preparation of l5-hydroxy-9-oxoprostanoic acid, ethyl ester A solution of g. of l5-(tert-butoxy)-9- oxoprostanoic acid, ethyl esterin 100 ml. of trifluoroacetic acid is stirred in an ice bath for 1 hour and is then poured into 500 ml. of ice water and extracted several times with chloroform. The combined chloroform extracts are washed with saturated sodium bicarbonate solution, saturated sodium chloride solution,

dried with anhydrous magnesium sulfate, and taken to dryness. The resulting oil is dissolved in 200 ml. of 1N ammonium hydroxide in ethanol, kept at ambient temperature for 15 minutes, then taken to dryness. The residual oil is dissolved in chloroform and washed with 1N hydrochloric acid, saturated sodium chloride solution, dried and taken to dryness to give 21.7 g. (100 percent) of product as a yellow syrup. There is essentially no uv absorption; A KBR/max 2,90, 5,75, 8,45 ;1.; nmr 2H quartet 8 4.13 (OCH of ester), 1H broad singlet 3.63 (carbinolic proton), 3H triplet (CH of ester) and 3H distorted triplet 0.92 (terminal methyl); mass spectrum: m/e 368.

18 EXAMPLE 51 Preparation of 3-(tert-butoxy)-l-iodohexane A mixture of 23.4 g. of 1-chloro-3-hexanol [Fourneau, et al., Bull. Soc. Chem. France, 25, 367 (1919)] in 300 ml. of 2-butanone containing g. of sodium iodide is stirred at the reflux temperature for 18 hours. The cooled solution is filtered and the mother liquor is taken to dryness. Distillation of the residue affords 32.9 g. (84 percent) of l-iodo-3-hexanol, b.p. 105C. (10 mm). Treatment of this material in 500 ml. of methylene chloride, containing 4 ml. of concentrated sulfuric acid, with isobutylene according to the procedure described in Example 48 gives 27 g. of crude material. Chromatography on florisil affords 16 g. of product; A,,,,,, 7.22 and 7.37 ,u.(tert-'butyl group.

EXAMPLES 52-70 Treatment of the various cyclopentenone esters listed in Table 11 below with the 3-t-butoxyalkyl magnesium iodide, also listed in the table, in the presence of tributylphosphine cuprous iodide complex all in the manner described in Example 49 above is productive of the l5-(tert-butoxy)-9-oxoprostanoates of the table.

EXAMPLES 71-89 Treatment of the various 15-tert-butoxyprostanoates of Table 3 below with trifluoroacetic acid in the manner of Example 50 above is productive of the corresponding l5-hydroxyprostanoates of the table.

TABLE 2 Grignard Reagent Product 15-( tert-butoxy 9-oxo-prostanoates Starting cyclopentenone of Example Example magnesium iodide Ethyl 9-OX6- 1 S-t-butoxy- 1 9,20-dinor- -prostanoatc 3-t-butoxyhexyl do. Ethyl 9-oxo-15-t-butoxy-5,6.7,19,20- -pcntanor-prostanoate do. Ethyl 9-oxo-15-t-butoxy-6,7,19.20- -tetranor-prostanoatc do. Ethyl 9-oxo-15-t-butoxy-7a,7b-bishomo- -19.20-dinor-prostanoate do. Ethyl 9-oxo-15-t-hutoxy-7.19,20-trinor- -prostanoatc do. Ethyl 9-oxol 5-t-butoxy-7a-homol 9.20-

-dinor-prostanoate do. Butyl 9-oxo-l5-t-butoxy-l9,20-dinor- -prostanoatc do. lsopropyl 9-oxo-l5-t-butoxy-l9,20-dinor- -prostanoate 3-t-butoxyhexyl Methyl 9-oxol S-t-hutoxy-19,20-dinormagnesium iodide -prostanoatc do. Decyl 9-oxo-15-t-butoxy-19,20-dinor- -prostanoatc 3-t-butoxyoctyl Ethyl 9-oxo-15-t-butoxy-5.6,7-trinormagnesium iodide -prostanoate do. Ethyl 9-oxo-15-t-butoxy-6,7-dinor- -prostanoate do. Ethyl 9-oxo-l5-t-butoxy-7a,7b-bishomo- -prostanoate do. Ethyl 9-oxo-l5-t-butoxy-7-nor-prostanoate do. Ethyl 9-oxo-l 5-t-butoxy-7a-homo- -prostanoate do. Butyl 9-oxo-l5-t-butoxy-prostanoate do. 'lsopropyl 9-oxo-15-t-butoxy-prostanoate do. Methyl 9-oxo-1S-t-butoxy-prostanoatc do. Decyl 9-oxo-l5-t-hutoxy-prostanoatc TABLE 3 TABLE 4-Continued Starting IS-tert- Starting l5- Product Ex- -butoxyprostanoates Product Exhydroxyprostanoate 9-oxol S-methanesulfonyloxyample of example lS-hydroXy-9-oxo-prostanoatcs 5 ample of example -prostanoatc 7] s2 Ethyl -uxO-l 5-hydroxy- 9.20- 93 73 Ethyl I h ne- -dinor-prostanoate y 0xy- .I9.20- 72 53 Ethyl 9-oxo-l5-hydroxy-5,6.7, r n0r-prostan0ate l9,20-pentanor-prostanoatc 94 74 Ethyl l 73 54 Ethyl 9-oxo-l5-hydroxy-6,7,l9, y Q yfl, QmO- ZO-tetranor-prostanoatc l0 l .2 -dln0r-prostanoatc 74 55 Ethyl 9-oxo-l5-hydroxy-7a,7h- 95 75 Ethyl 5-me hflneqggu sulfonyloxy-7.l9,20-trinor- PTOSIHHOZHC -pr0stanoate 7s 56 Ethyl 9-oxo-l5-hydroxy-7,l9. 96 76 Ethyl 9-0X0-15-melhune- ZO-trinor-prostanoatc sulfonyloxy-7a-homol 9,20- 76 57 Ethyl 9-oxo-l5-hydroxy-7a- -dmor-pr tan0ate -homo-l9,20-dinor-prostanoate 97 77 B yl -0X0-l5-methane- 77 58 Butyl 9-oxo-l5-hydroxy-l9,2()- s ny xy-l9.20-dinor- -dinor-prostanoatc V 'prostanoate 78 59 l l 9. |5.hyd 98 78 lsopropyl-9-oxo-l5-methane- -l9,20-dinor-prostanoate sulfonyloxy-l),20-dinor- 79 60 Methyl 9-oxo-l5-hydroxy- -prostanoate -l9 2()-din rm r 99 79 Methyl 9-oxo-l5-methane- 80 M Decyl 9-oxo-l5-hydroxy-l9,2l)- Sulfonyloxy-l9,20-dinor- -dinor-prostanoate -prostanoate ill 62 Ethyl 9-oxo-l5-hydroxy-5,6,7- 100 80 Decyl 9-oxo-l5-methane- -trinor-prostanoatc sulfonyloxy-l),20-dinor- 82 63 Ethyl 9-oxo-I5-hydroxy-6J- -prostanoate -dinor-pmstanoate I01 8] Ethyl 9-oxo-l5-methanc- 83 64 Ethyl 9-oxo-l5-hydroxy-7a.7bsulfonyloxy-S.6.7-trinor- -bishomo-prostanoate 2 5 -prostanoatc 84 65 Ethyl 9-oxo-l5-hydroxy-7-nor- 102 82 Ethyl 9-oxo-l5-mcthane -prostanoate sulfonyloxy-6,7-dinor- 85 66 Ethyl 9-oxo-l5-hydroxy-7a- -prostanoate -h m m I03 83 Ethyl 9-oxo-l5-methanc- 86 67 Butyl 9-oxo-l 5-hydroxysulfonyloxy-7a.7b-hishomo -prostanoatc -pr0stan0ate 87 68 lsopropyl 9-oxo-l5-hydroxy- I04 84 Ethyl 9-0X0-l5-metane- -prostanoate sulfonyloxy-7-nor- 88 69 Mcthyl 9-oxo-l5-hydroxy- -prostanoate m mn 105 85 Ethyl 9-oxo-l5-methane- 89 70 Decyl 9-oxo-l5-hydroxysulfonyloxy-7a-homo- -prostan0ute -prostanoatc I06 86 Butyl )-oxo-l5-methancsulfonyloxy-prostanoate I07 87 lsopropyl 9-oxo-l5-mcthanc sulfonyloxy-prostanoatc Preparation of ethyl 10s as Methyl 9oxo-l5-mcthanc- X r at sultonyloxy-prostanoate l5 methanesulfonyloxy 9 0 0 p osta I09 89 Day] gomlsmcthuw To a stirred solution of 2.48 g. of ethyl l5-hydroxy-9- y-p oxo-prostanoate (Example 50) in 18 ml. of methylene chloride containing 1.4 ml. of triethylamine, cooled in an ice-salt bath is added dropwise 0.58 ml. of me- EXAMPLE 1 10 thanesulfonyl chloride. The resulting mixture is stirred for l5 minutes and is then washed successively with ice PrePaTam of ethyl l5"izldo'9'oxo'prostdnodte cold water, 10 percent hydrochloric acid, saturated so- A Solution of 1.35 g. of ethyl l5-methanesulfonyloxy dium bicarbonate solution, and saturated sodium chlo- 9- 0-P fi a P in 6 mlof ride solution. dried with anhydrous magnesium sulfate N.N-dimethyl-formamide containing 1.25 g. of sodium and taken to dryness to give 2.7 g. (90 percent) of oil; azide is heated on the steam-bath for 18 hours. The X 5.78 (carbonyl groups), 7.45 and 8.55 a (sulfocooled solution 18 poured mto 300 ml. of water and the nate). resulting mixture is extracted several times with ether. The combined ether extracts are washed with saturated EXAMPLES 91-109 sodium chloride solution, dried with anhydrous magne- T atment of the various l5-hydroxyprostanoates slum sulfate and taken to dryness. The residual oil is listed in Table 4 below with methylenesulfonyl chloride chromatographed slllca g to give 737 g- P in accordance with the procedure of Example 90 above cent) of Mm. and M (Carbonyl is productive of the lS-methanesulfonyloxyprostanate g p Of the table. ,7 111 TABLE 4 Preparation of ethyl l5-chloro-9-oxo-prostanoate A s lu l smmng Product 9 0 ton of l 35 g of ethyl 15 methanesulfonyloxy Exhydroxyprostanoatc 9-oxo-l5-methancsulfonyloxy- 'oxo'prostanoate (E p m 40 1111- O ample Ofexumplc rmswnvmc N,N-dimethyl-formamide containing 650 mg. of lith- 71 Ethyl ium chloride [5 heated on the steam bath for 18 hours.

sull'onyloxy-l9 2()-dinor- The cooled solution 15 diluted with water and the resultrostanoatc 92 72 my] 9mm smmhuw mg mixture 15 extracted with ether. The ether extract sult'onYloxy-Sgta], l 9,20- -pentanor-prostanoatc is washed with saline, dried with saline, dried with anhydrous magnesium sulfate and evaporated to dryness to give an oil. Chromatography on silica gel affords an oil; X 5.78 p. (carbonyl groups).

EXAMPLE 1 12 Preparation of ethyl 9-oxo-lS-thiocyano-prostanoate EXAMPLE 113 Preparation of ethyl l5-acetylthio-9-oxo-prostanoate A solution of 1 g. of ethyl l5-methanesulfonyloxy-9- oxo-prostanoate (Example 90) in 50 ml. of acetone containing 735 mg. of purified potassium thiolacetate is kept at the reflux temperature for 2 hours, then at room temperature for 18 hours. The mixture is diluted with water and the resulting solution is washed with saturatcd sodium chloride solution, dried with magnesium sulfate and taken to dryness. The residue is chromatographed on silica gel to give an oil; X,,,,,, 5.78 (ring carbonyl and ester group) and 5.92 p. (acetylthio group).

EXAMPLE ll4-l42 Treatment of the l5-methanesulfonyloxyprostanoates listed in Table 5 below with the indicated reagent, by the methods describing examples 110 (for sodium azide), lll (for lithium chloride), 112 (for potassium thiocyanate) or l 13 (for potassium thiolacetate) is productive of the l5-substituted prostanoates of the Table.

TABLE 5 Starting 15-methanesulfonyloxy prostanoates Product 9-oxo-15-substituted- Ex. of example- Reagent prostanoate 114 91 NaNa Ethyl 9-oxo-15-aztdo-19,20-

dinor-prostanoate. 4 5 115 94 NaNa Ethyl 9-oxo-l5-azldo-7a,7b-

bIshorno-19,20-dlnorprostanoate. 116 05 NaNa Ethyl 9-oxo-15-azldo-7,10,20

trlnor-prostanoata. 117. 100 NaNz Decyl 9-oxo-15-azldo-19,2t%

dlnor-prostanoate. 118 102 NaNa Ethyl 9-ox0-15-azld0-6,7- 5 0 dlnor-prostanoate. 119 103 NaNa Ethyl 9-oxo-15-azldo-7a,7b-

blshomo-prostanoate. 120- 104 NaN Ethyl 9-oxo-15-azido-7-norprustanoate. 121 Ethyl 9-oxo-15-azido-7a-homoptostanoate. 122 106 NaN; Butyl 9-oxo-l5-azidoprostanoates. 5 5

123 91 O Ethyl 9-oxo-15-acetylthio-19,

20-dinor-prostanoate. CHaC-SK 124. 92 Same as above- Ethyl 9-oxo-15-acetylthto-5,

6,7,19,20-pentenorprostanoate. 60 125 96 -do Ethyl 9-oxo-15-acatylthlo-7ahomo-19,20-d1norprostanoate. 126 99 -do Methyl 9-oxo-li-aeetylthto- 19,20-dlnor-prostanoate. 127 101 .do Ethyl 9-0xo-15-acetylthio- 7-nor-prostanoate. 128- 105 do Ethyl 9-ox0-15-acetylthlo- 6 5 7-homo-prostanoate. 129 108 -do Methyl 9-0xo-15-acetylth1oprostanoate. 130 91 LlCl Ethyl 9-oxo-15-chloro-l9,20-

dtnor-prostanoate. 131 99 Li Cl Methyl-9-oxo-15-chloro-19,20-

dinor-prostanoate. 132 93 L101 Ethyl 9-oxo-15-chloro-6,7,19,

20-tetranor-prostanoate.

TABLE 5 Continued Starting IS-methanesulfonyloxy prostanoates Product 9-oxol S-substituted- -Ex. of example- Reagent prostanoate 133.-. 97 L101 But-yl 9-oxo-15chloro-19,20-

dlnor-prostanoate. 134.-. 102 L101 Ethyl 9-oxo-l5-chloro-6,7-

dlnor-prostanoate. 135. 108 LiCl Methyl 9-oxo-15-ch1oroprostanoate. 136... 105 L101.-. Ethyl 9-ox0-15-chlorohomo-prostanoate. 137-.- 98 KCNS Isopropyl 0-ox0-15-thlocyano- 19,20dln0r-prostanoate. 138--. 101 KCNS Ethyl -oxo-lfi-thlocyano- 5,6,7-trlnor-prostanoate. 139... 103 KCN S Ethyl 9-oxo-15-thlocyano- 7a,7b-bishomorostanoate. 140... 95 KCNB Ethyl 9-oxo-l5-th ocyano- 7,19,20-trlnor-prostanoate. 141... 107 NaN; 1sopropyl9-oxo-15-azldoprostanoate. I 142..- 109 NaNa Decyl 9-oxo-15-azidoprostanoate.

EXAMPLES l44-l54 Hydrogenation of the various l5-azidoprostanoates listed in Table 6 below by the method described in Ex-.

ample 143 provides the l5-amin0-pr0stanoates of the Table.

TABLE 6 Starting lS-azido Exprostunoute of Product ample Example 7 9-oxol S-amino-prosttmoutc I44 I I4 Ethyl 9-oxo-l5-umino-l9.2(l-

-dinor-prostunoatc I45 I I5 Ethyl 9-oxo-l5-umino-7u,7b-

-hishomn-l9,20-dinor- -prostunoute I46 I16 Ethyl 9-oxo-l5-umino-7,l9,2()-

-trinor-prostanmitc I47 1 l7 Decyl 9-oxo-l5-umino-l9,20-

-dinor-prostunontu 148 1 l8 Ethyl 9-oxo-l5-umino-6J -dinor-prostnnoutc I49 ll) Ethyl 9-oxo-l5-amino-7a.7h-

-bishomo-prostanoutc I50 I20 Ethyl 9-oxo-l5-amino-7-nor- -prostunoatc l5l l2l Ethyl 9-oxo-l5-umino-7a-homo- -prostanoate I52 I22 Butyl 9-oxo-l5-amino- -prostan0utc l53 l4l lsopropyl 9-oxo-l5-amino- -prostanoate EXAMPLE Preparation of ethyl 9-oxo-lS-mercapto-prostanoate A solution of 606 mg. of ethyl l5-acetylthio-9- oxoprostanoate (Example H3) in 20 ml. of reagent methanol is treated, under nitrogen atmosphere, with 1.6 ml. of 1N methanolic sodium methoxide. After 10 minutes the reaction is quenched by the addition of 0.3 ml. of glacial acetic acid and taken to dryness. A solution of the residue in ether is washed with saturated sodium chloride solution, dried with anhydrous magne- 23 sium sulfate and taken to dryness to afford 428 mg. (89 percent) of an oil; A,,,,, 4.0 (sulfhydryl) and 5.78 p. (carbonyls EXAMPLES 156-162 Brief treatment of the various l-acetylthioprostanoates listed in Table 7 below with methanolic methoxide by the method described in Example 155 immediately preceding is productive of the l5-mercapto-prostanoates of the Table.

TABLE 7 Starting IS-acetyl- -prostanoatc EXAMPLE 163 Preparation of l5-azido-9-oxo-prostanoic acid A suspension of 880 mg. of ethyl l5-azido-9-oxoprostanoate (Example 110) in ml. of methanolwater 1:1 containing 360 mg. of potassium hydroxide is stirred at ambient temperature for'18 hours. The resulting solution is acidified with dilute hydrochloric acid and the oily layer is taken up in ether. The ether is washed with saturated sodi sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 797 mg. (98 percent) of an oil; A,,,,,, 3.0-3.5 broad (acid group), 4.88 (azido group), 5.78 and 5.90 (carbonyl groups).

EXAMPLES 1 64-1 75 Saponification of the various prostanoic esters listed in Table 8 below is productive of the corresponding acids listed in the table prostanoic acid 24 TABLE 8 Continued Starting pro- Product stanoate ester l5-substituted-94)xo-proslanoic Example of Example acid 135 9-oxu-15-chloro-prostanoic acid 176 71 9-oxo- 1 S-hydroxy- 19.2(1-dinor- -prostanoic acid 177 72 9-oxo 15-hydroxy-5.6.7,19.211-

-pcntanor-prostanoic acid 178 73 9-uxo-l 5-hydroxy-6.7. 19,20-

-tctranor-prostanoic acid 179 74 9-oxo-15-hydroxy-7a.7h-hishomt -19.20-dinor-prostanoic acid 180 75 9-oxo-l5-hydroxy-7,19.20-trinor- -prostanoic acid 181 76 9-oxo-15-hydroxy-7a-homo-19.

ZO-dinor-prostanoic acid 182 81 9-oxo-15-hydroxy-5.6,7-trinor -prostanoic acid 183 82 9-oxo-l 5-hydroxy-6.7-dinor- -prostanoic acid 184 83 9-oxo-15-hydroxy-7a.7h-bishomo-prostanoic acid 185 84 9-oxo-15-hydroxy-7-nor- -prostanoic acid 186 50 9-oxo-1S-hydroxy-prostanoic acid EXAMPLE 187 Preparation of 901,1S-dihydroxyprostanoic acid To a solution of 433 mg. of 15-hydroxy-9-oxoprostanoic acid (Example 186) in 4.5 ml. of tetrahydrofuran, stirred in an ice-bath under nitrogen atmosphere, is added dropwise 3.7 ml. of 0.76 M lithium perhydro-9b-boroaphenalyl-hydride. After 40 minutes at 0C. there is added 1.62 ml. of 3N sodium hydroxide followed by 1.62 ml. of 30 percent hydrogen peroxide. Ether is added and the resulting solution is acidified with 2N hydrochloric acid. The ether layer is washed several times with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 300 mg. (70 percent) of waxy solid; nmr 3H singlet 5 4.64 (hydroxyl and carboxyl protons), l H singlet 4.22 (9B-carbinolic proton, 80 percent), 1 H singlet 3.88 (9a-carbinolic protons, 20 percent), 1 H singlet 3.61 (IS-carbinolic proton), and 3 H distorted triplet 0.90 (terminal methyl).

EXAMPLES 188-203 Treatment of the various 9-oxoprostanoic acids listed in Table 9 below with lithium perhydro-9bboraphenalyl hydride by the procedure described in Example '187 is productive of the 9a-hydroxy derivatives of the table.

TABLE 9 Starting 9-oxo- -19.20-dinor-prostanoic acid TABLE 9-Continued TABLE lO-Continued Starting 9-oxo- Starting 9-oxo- Ex- -prostanoate of Product EX- -prostanoate of Product ample Example 9u-hydroxy-prostano ample Example 9whydroxy-prostanoate 197 i so 981i s dih dmx -i. 1 920- 5 228 144 Ethyl 9a-hydroxy- 1 S-amino- -trinor-prostanoic acid l 9.ZO-dinor-prostunoatc l98 l8l 9a.]5-dihydroxy-7a-homo-l9. 229 I45 Ethyl )a-hydroxy-lS-amino- ZO-dinor-prostanoic acid -7a,7h-hishomo-l9.20-tlinor- I99 I82 901.15-dihvdrxy-5.6.7-trinor- -pr0$tan0alc mmmi'c a id 230 I46 Ethyl 9a-hydroxy-l5-amino- 200 [83 90:. l -dihydroxy-6,7-dinor- -7. l 9.2(l-trinor-prostanoatc m i id TH I47 Dccyl )a-hydroxy-lS-aminu- 184 901. l 5-dihydroxy-7a.7hl 9.ZO-dinor-prostanontc bighnmo-prustanuic add 232 148 Eihyi 9ah vdroxy-lS-amino- )2 lR5 90. l 5-dihvdroxv-7-nor-pro- -6.7-dinor-prostanontc stanoic ac id 233 l4) Ethyl )a-hydroxydS-amino- 203 I86 911. l 5-dihydroxy-7a-homo- -7a.7h-hishonto-prostanoate m i id 234 l5() Ethyl 9a-hydroxy-lS-aminol5 -7-nor-prostanoate 235 I5] Ethyl 9a-hydroxy-l5-amino- EXAMPLE 204 -7a-homo-prostanoatc 236 152 Butyl )a-hydroxy-lS-amino- Preparauon of ethyl 901,15-d1hydroxyprostan0ate ethyl -prostanoatc star 237 I53 lsopropyl-Qa-hydroxy-l5-am1noe 20 -prostanoate 33 1. Treatment of l5-hydroxy-9-oxoprostano1c acid, ethyl 8 ZjgglJfgJg ester in tetrahydrofuran with 0.76M lithium perhydro- 239 155 Ethyl )u-hydroXy-lS-mercapto- -PI'OS!HHOHIC 9b bo raph enalylhydrlde accordmg to the procedure 240 I 56 my] gwhydmxyd descr1bed 1n Example 187 gives an oily product; A -l9,20-dinor-prostanoatc 4 I 24] I57 Ethyl 9a-hydroxy-lS-mcrcapto- 2 5 8 5 M 5.6.7.l9.2(l-pentanor- -prostanoatc EXAMPLE 205-246 242 I58 Ethyl Jot-hydroxy-lS-mcrcapto- 9 20- Treatment of the 9-ox0- prostanoate esters of Table 10 below with lithium perhydro-9b-boraphenalyl hy- 243 159 Mgt hyldJa-hydroxy-l5-mercaptn- -l ..(linor-prostanoatc dr1de by the procedure of Example 204 is productlve 244 I60 Ethyl 9a hydmxy |5 mercupm of the 9a-hydroxy-prostanoates of the table. -prostano- -7-nor-prostanoatc 245 lbl Ethyl Qa-hydroxy-lS-mcrcaptoate -7-hnmo-prostanoate TABLE 10 246 I62 hglcthlya'llnzgiydroxy-l5-mercapto- Starting 9-oxo- Ex- -prostanoate of Product ample Example )u-hydroxy-prostanoatc EXAMPLE 247 205 71 l y y Preparation of ethyl 9a/,B,lS-dihydroxyprostanoate lI'lOr-PI'OS an oa C 206 72 Ethyl y y-5.6.7. A solut1on of 3 g. of ethyl l5-hydroxy-9-oxol9.20-pentanor-prostan oate 207 73 Ethyl 9a5 dihydm,(y 6 7'|9 prostanoate (Example 1n 120 ml. of absolute alcolfl-tetrano -p psw m hol containing 1 15 mg. of sodium borohydride is stirred 74 i g zfgl 'gffinfi at ambient temperature for 18 hours. The solution is prostanoate poured into 300 ml. of saturated sodium chloride solu- 209 75 yl 911-1 y tion and the oily precipitate is extracted'with ether. The

2()-tr1nor-prostanoate 2m 76 Ethyl 9a'|5 dihydmxy 7a ether phase is washed with saturated sodium chlorlde 7 I 77 3 7- ifg-gjg g-p a gg solution, dried with anhydrous magnesium sulfate and 1, taken to dryness to give 2.74 g. of an oil; a 2.95, 212 vs lsopropyl 9a,l5-dihydroxy-l9. 5.78, 8.45 ,1/.; the product is a mixutre of 9aand 9B- ZO-dinor-prostanoatc 213 79 Methyl 9a.l5-dihydroxy-l9.20- 50 hydroxy denvatwes -dinor-prostanoate 214 80 Decyl 9a.l5-dihydroxy-l9,20-

-dinor-prostanoate 5 EXAMPLES 248 251 7 3 $lff$i$fi Treatment of the 9-oxo-prostanoates listed 1n Table 21a '82 Ethyl 9a.l5-dihydroxy-6.7- 55 II below with sodium borohydride by the procedure de- 2l7 83 g fifi gf ffif scribed in Example 247 is productive of the mixture of -bishomo-prostanoate 9aand 9B-hydroxy-prostanoates of the Table. 218 84 Ethyl 9a,]5-dihydroxy-7-nor -prostan0atc 2l9 85 Ethyl 911.15-dihydroXy-7a- 1 1 homo-prostanoate 220 86 Butyl 9a,l5-dihydroxy- 60 'Pwsmnome Starting 9-ox0- 22] 87 P PY y y' Ex- -prostanoate Product 'prostanomc ample of Example 9a/9fl-hydroxy-prostanoate 222 88 Methyl 9a.]5-d1hydroxy- -prostanoate 224 Ethyl a-hydroxy-lS-azido- 65 248 g g f fgfi -prostanoatc 225 111 Ethyl 9a-hydroxy-l5-chloro- 249 F' z fz hydmxy ch10 250 143 E 1h 1 9a/ZlB-hydroxy- 1 S-amino- 226 I I4 Dccyl 9a-hydroxy-l5az1do-- Pmsmnoate 251 15s Ethyl 9u/9Bhydroxy-l 5- 227 l4? Ethyl 9ahydroxy-l5-amino- I H l p tu a' -mercapto-prostanoatt.

Saponification of the 9a/9,8-hydroxy prostanoates of Table 12 below by the method described in Example 163 is productive of the prostanoic acids of the Table.

TABLE 12 Starting prostanoates Product Example of Example 9a/9fi-hydroxy-prostanoic acid 252 248 9a/9fi-hydroxy- 1 5-azido- -prostanoic acid 53 249 9a/9B-hydroxyl 5-chloro- -prostanoic acid 254 251 9a/9B-hydroxy- I S-mcrcapto- -prostanoic acid EXAMPLE 255 Preparation of l5-amino-9 oxoprostanoic acid hydrochloride EXAMPLES 256-271 Ester hydrolysis of the lS-amino-prostanoates listed in Table 13 below by the procedure described in Exam- -ple 255 is productive of the IS-amino-prostanoic acid hydrochlorides of the Table.

TABLE 13 Starting IS-amino- Product Ex- -prostanoatc of l5-amino-prostanoic acid ample Example hydrochloride 256 144 9-oxo-15-amino-l9.20-dinor- -prostanoic acid-HCl 257 145 9-oxo-l5-amino-7a,7b-bishomo-19,20-dinor-prostanoic acid-HCl 258 146 9-oxo-l5-amino-7,l9.20-

-trinor-prostanoic acid-HCl 259 148 9-oxo-l5-amino-6,7-dinor- -prostanic acid'HCl 260 149 9-oxol -amino-7a,7b-bishomo- -prostanoic acid-HCl 261 150 9-oxol 5-amino-7-nor- -prostanoic acid'HCl 262 151 9-oxol 5-amino-7a-homo- -prostanoic acid'HCl 263 227 9a-hydroxy-l5-aminoprostanoicacid'HCl 264 228 9a-hydroxy-l5-amino-19,20-

-dinor-prostanoic acid'HCl 265 229 9a-hydroxy-15-amino-7a,7b-

bishomo-19,20-dinor- -prostanoic acid'HCl 266 230 9a-hydroxy-l5-amino-7.l9.20-

-trinor-prostanoic acid'HCl 267 232 9a-hydroxy-l5-amino-6.7-

-dinor-prostanoic acid'HCl 268 233 9a-hydroxy-l5amino-7a.7b-

-hishomo-prostanoic acid'HCl 269 234 9a-hydroxy-15-amino-7-nor- -prostanoic acid'HCl 270 235 9a-hydroxyl 5-amino-7a-homo- -prostanoic acid 271 250 9a/9B-hydroxy- 1 S-amino- -prostanoic acid'HCl 28 EXAMPLE 272 Preparation of 9B,1S-dihydroxyprostanoic acid A solution of ethyl 9,8, l S-dihydroxyprostanoate in 32 5 ml. of methanol-water 1:1), containing 890 mg. of potassium hydroxide is kept at ambient temperature for 18 hours. The solution is acidified with dilute hydrochloric acid and extracted several times with ether. The ether phase is washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 1.63 g. of an oil; nmr 3H singlet 85.53 (hydroxyl and carboxyl protons). 1H singlet 4.23 (9,8-carbinolic proton. 30 percent). 1H singlet 3.90 (9a-carbinolic proton, 70 percent), 1H singlet 3.65 (15-carbinolic proton), and 3H distorted tirplet 0.90

(terminal methyl).

EXAMPLE 273 Preparation of methyl ll 5 S )-acetoxy-9-oxo-prostanoate A solution of 2.5 g. of methyl l5(S)-acetoxy-9-oxo-5- cis, 10,13-trans-prostatrienoate [W. P. Schneider, R.

EXAMPLE 274 Preparation of methyl ll 5 S )-hydroxy-9-oxo-prostanoate A solution of 2.26 g. of methyl l5(S)-acetoxy-9-oxoprostanoate (Example 15) in 300 ml. of absolute alco- 40 hol containing 790 mg. of potassium carbonate is stirred at ambient temperature for 72 hours then concentrated to near dryness under reduced pressure. The resulting mixture is extracted with ether. The combined extracts are washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 1.83 g. of an oil. Purification by silica gel chromatography affords the subject compound as an oil; A 2.92 (hydroxyl group), 5.74 t (carbonyl groups); [a],, 23C. (0.2 percent in Cl-lCL EXAMPLE Preparation of l-l5-(S)-hydroxy-9-oxo-prostanoic acid We claim: l. A compound selected from the group consisting of those of the formula:

H1 H CH 40H;

wherein R is selected from the group consisting of hydrogen and an alkyl group having from I to 12 carbon atoms, and Y is a divalent radical selected from the group consisting of those of the formulae:

0 HO H OH hydrogen and Y is l-9-oxol 5(S )-amino-prostanoic acid.

3. The compound according to claim 1 wherein R is ethyl and Y is o l I l-ethyl 9-oxo-l 5 S )-amino-prostanoate.

4. The compound according to claim 1 wherein R is hydrogen and Y is 1-9 oz-hydroxyl 5(S )-aminoprostanoic acid.

5. The compound according to claim 1 wherein R is hydrogen and Y is 30 l-9B-hydroxy-l 5(S)-aminoprostanoic acid.

6. The compound according to claim 1 wherein R is n-pentyl and Y is l-n-pentyl 9-oxol 5( S )-aminoprostanoate.

7. The compound according to claim 1 wherein R is n-nonyl and Y is o I a Y l-n-nonyl 9-oxol 5(S )-aminoprostanoate.

8. The compound according to claim 1 wherein R is n-pentyl and Y is l-n-pentyl 9,8-hydroxyl 5 S)-aminoprostanoate.

9. The compound according to claim 1 wherein R is methyl and Y is 1 -methyl 9l3-hydroxy-15(S)-aminoprostanoate.

10. The compound according to claim I wherein R is methyl and Y is l-methyl 9a-hydroxyl 5 (S )-aminoprostanoate.

a UNITED sTATEs- PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,835,179 1 Dated September 10, 1974 n fl 'Robe rt Eugene Schaub, Martin Joseph Weiss It is certified that error appears in the above-identified patent and that said'Letters Patent are hereby corrected as shown below:

HO ,H nor H Column 29, Claim 4 C should be C I .Ho; H HO H Column 29, Claim 5 C should be C;

110; H v g /H Column 30 Claim 8 C should be a C Signed and sealed this 3rd day of December 1974.

(SEAL) Attest: McCOY M. GIBSON JR. 'c.' MARSHALL DANN Attesting Officer Commissioner of Patents Form Po-mso uo-ss) USCOMM DC GO376-P69 U. S GOVIINIINT IIINTIIIG OFFICE I", O-Ill-IM 

2. The compound according to claim 1 wherein R is hydrogen and Y is
 3. The compound according to claim 1 wherein R is ethyl and Y is
 4. The compound according to claim 1 wherein R is hydrogen and Y is
 5. The compound according to claim 1 wherein R is hydrogen and Y is
 6. The compound according to claim 1 wherein R is n-pentyl and Y is
 7. The compound according to claim 1 wherein R is n-nonyl and Y is
 8. The compound according to claim 1 wherein R is n-pentyl and Y is
 9. The compound according to claim 1 wherein R is methyl and Y is
 10. The compound according to claim 1 wherein R is methyl and Y is 